Abstract: Waterpipe smoking in the US is on the rise and beginning to overtake cigarettes as the most popular method of tobacco use among young adults. Unfortunately, waterpipe smoking is associated with many of the same negative health outcomes as cigarette use such as cancer, lung disease, respiratory illness, and cardiovascular disease. A potential reason for the appeal of waterpipe tobacco is that it is almost exclusively flavored with both sweeteners and additional fruit, candy, savory and dessert flavorings. The Family Smoking Prevention and Tobacco Control Act which banned flavors, except menthol, from cigarettes due to scientific evidence indicating that flavors increased youth initiation and maintained use among adults, does not currently apply to waterpipe tobacco. As a result, waterpipe tobacco is currently unregulated and comes in hundreds of flavors. In order to regulate waterpipe tobacco effectively, the FDA requires clear scientific evidence to support regulations. To date, no study has experimentally and systematically investigated the impact of waterpipe tobacco flavors on waterpipe initiation, smoking behaviors, abuse liability, or resultant exposure to tobacco- related toxicants. The proposed study will provide this needed scientific evidence. Using a randomized crossover-design, 60 current waterpipe smokers (30 low dependent, 30 high dependent) will complete three counterbalanced waterpipe smoking sessions with three differently flavored tobacco (preferred flavor- sweetened, unflavored-sweetened, unflavored-very low sweetened) that are preceded by 12 hours of tobacco/nicotine abstinence. Sessions will be separated by a standard 48-hour washout period, and waterpipe tobacco nicotine levels will be held constant across sessions. Measures of smoking behavior (puff topography) and acute toxicant exposure (CO boost and plasma nicotine) will be collected, in addition to self-report measures of abuse liability, intentions for continued use, and importance of flavors for using waterpipe. If flavorings are determined to influence users to initially try waterpipe, increase their willingness to continue to use the product, and/or make it more palatable to puff more frequently or take longer/deeper puffs, then flavors would be contributing to the initiation and maintenance of waterpipe dependence. This innovative study in its systematic examination of the impact of waterpipe flavors, will provide the scientific foundation the FDA and other agencies need to establish effective regulatory strategies for the manufacture, distribution, and marketing of waterpipe tobacco.